A gene defect that causes a hereditary liver disease and its harmful effects on cells has been successfully corrected by researchers at the University of Helsinki and HUS Helsinki University Hospital.
Argininosuccinate lyase deficiency (ASLD), also known as argininosuccinic aciduria, is a disease that is prevalent in the Finnish genetic heritage. This severe metabolic disease disrupts the normal processing of proteins in the body, leading to a range of harmful effects.
Argininosuccinic acid and ammonia can accumulate dangerously in the body, leading to disturbances of consciousness, coma, and potentially death.
Infants in Finland undergo screening for ASLD to identify disease risk before symptoms appear. Treatment involves a strict lifelong diet and, in severe cases, a liver transplant.
Researchers from the University of Helsinki and HUS Helsinki University Hospital have successfully corrected the gene defect associated with argininosuccinic aciduria, demonstrating that the harmful metabolism caused by the disease can be cured.
Their recent study focused on initially modifying the gene defect in order to treat ASLD.Researchers used the CRISPR-Cas9 technique to reprogram the gene defects in stem cells derived from the skin cells of ASLD patients. The goal was to see if this gene correction would result in the cells no longer producing harmful argininosuccinic acid and if the hepatic function would be restored. The study showed that the gene defect causing ASLD can be corrected with gene scissors without any adverse effects visible in the cells. This marks a significant advancement in potential treatment for ASLD.cells were also improved metabolically, according to Docent of Stem Cell Biology Kirmo Wartiovaara, an expert in medical genetics at the University of Helsinki and HUS. The study was published in the American Journal of Human Genetics. Researchers have found a suitable “gene mixture” in a drug that is already in use. In the study, the researchers used mRNA encapsulated in lipid nanoparticles to introduce the gene scissors into the cultured cells. The “gene mixture” produced is based on the formula of a pharmaceutical product that is already in use, which may facilitate its use.s clinical use in the future. Our next goal is to cure ASLD in mice,” says Doctoral Researcher Timo Keskinen from the University of Helsinki.
“The same gene editing technique works on living animals and humans, but we don’t yet know how safe it is. This is why the matter has to be investigated first in laboratory animals,” Keskinen adds.
Therapeutic potential at last for hereditary diseases
There are already more than 7,000 hereditary diseases in the world. Finns, as well as other populations originating in small groups of people, have their own genetic disease variants that are more common in the population.ion than in any other part of the world. Many of these gene variants originated from our distant ancestors. If a child inherits the same variant from both parents, they may develop a severe disease.
There are treatments available for only a few hereditary diseases, and curative therapies are even rarer.
“However, a cure may be possible if the gene defect causing the disease is entirely eliminated. Thanks to basic research conducted with the help of gene scissors and other precise gene-editing techniques, permanent fixes are gradually beginning to emerge,” Wartiovaara says.
The study is part of the doctoral theses of SSami Jalil and Timo Keskinen, who work under the supervision of Docent Kirmo Wartiovaara and Mervi Hyvönen, DMedSc at the Biomedicum Stem Cell Center of the Biomedicum Helsinki research institute, recently conducted a study on genetic and functional correction of argininosuccinate lyase deficiency using CRISPR adenine base editors. Â
